YTHDF1 and YTHDF2 are associated with better patient survival and an inflamed tumor-immune microenvironment in non-small-cell lung cancer

被引：85

作者：

Tsuchiya, Kazuo ^{[1
,2
]}

Yoshimura, Katsuhiro ^{[1
,2
]}

Inoue, Yusuke ^{[1
,2
]}

Iwashita, Yuji ^{[1
]}

Yamada, Hidetaka ^{[1
]}

Kawase, Akikazu ^{[3
]}

Watanabe, Takuya ^{[4
]}

Tanahashi, Masayuki ^{[4
]}

Ogawa, Hiroshi ^{[5
]}

Funai, Kazuhito ^{[3
]}

Shinmura, Kazuya ^{[1
]}

Suda, Takafumi ^{[2
]}

Sugimura, Haruhiko ^{[1
]}

机构：

[1] Hamamatsu Univ Sch Med, Dept Tumor Pathol, Hamamatsu, Shizuoka, Japan

[2] Hamamatsu Univ Sch Med, Dept Internal Med, Div 2, Hamamatsu, Shizuoka, Japan

[3] Hamamatsu Univ Sch Med, Dept Surg 1, Hamamatsu, Shizuoka, Japan

[4] Seirei Mikatahara Gen Hosp, Resp Dis Ctr, Div Thorac Surg, Hamamatsu, Shizuoka, Japan

[5] Seirei Mikatahara Gen Hosp, Dept Pathol, Hamamatsu, Shizuoka, Japan

来源：

ONCOIMMUNOLOGY | 2021年 / 10卷 / 01期

基金：

日本学术振兴会;

关键词：

Lung cancer; ythdf1; ythdf2; pd-l1; tumor-immune microenvironment; m6A; IN-SITU HYBRIDIZATION; RNA; CLASSIFICATION; M(6)A; ADENOCARCINOMA; ANTIBODIES; EGFR;

D O I：

10.1080/2162402X.2021.1962656

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The human YTH domain family (YTHDF) proteins are RNA-binding proteins that recognize N6-methyladenosine (m6A), facilitating various biological processes via m6A RNA modification. How these molecules associate with non-small-cell lung cancer (NSCLC) molecular mechanisms remain unclear. The protein expression levels of YTHDF1 and YTHDF2 in 603 cases of resected NSCLC were evaluated using immunohistochemistry. We analyzed the associations of these attributes with patient characteristics and survival. We also assessed four subsets of lymphocytes (PD-1+, CD8+, Foxp3+, and CD45RO+) as tumor-infiltrating lymphocytes (TILs) in the tumor nest and in the surrounding stroma separately. In addition, we investigated differentially expressed genes and the expression of PD-L1 in YTHDF1- and YTHDF2-deprived lung cancer cells. The expressions of both YTHDF1 and YTHDF2 were less in the advanced-stage tumors than in the early-stage tumors. The expressions of both YTHDF1 and YTHDF2 were also independent favorable prognostic factors for recurrence-free survival (HR, 0.745; 95% CI, 0.562-0.984 for YTHDF1; HR, 0.683; 95% CI, 0.503-0.928 for YTHDF2). The TIL densities of almost all four lymphocyte subsets in the stroma were significantly higher in the tumors with high YTHDF1 and YTHDF2 expression. In vitro, YTHDF1 and YTHDF2 knockdown in cells upregulated tumor PD-L1 expression and altered multiple immune-related genes. High expressions of both YTHDF1 and YTHDF2 are associated with a favorable prognostic outcome of NSCLC patients, a greater amount of TILs, and downregulation of PD-L1. YTHDF1 and YTHDF2 could be novel prognostic and druggable targets related to the tumor-immune microenvironment in lung cancers.

引用

页数：13

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[1] Adjust for Multiple Comparisons? It's Not That Simple [J].